The drug discovery market remains untapped with huge potential for new breakthroughs and innovations in creating better medicines. Researchers are actively exploring innovative approaches to overcome the challenges inherent in drug discovery. One such avenue in the field of integrins offers a unique opportunity to draw insights from past clinical trials, delve into new modalities and integrate the latest discoveries in pharmacology.

Recent developments highlight novel inhibitors of the integrins αvβ6 and αvβ1, emerging as subjects of clinical investigation for treating fibrotic diseases like idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. Integrin inhibition has resulted in a number of commercial medications, as well as ongoing preclinical research. Since 2015, at least 130 clinical studies of integrin-targeted therapeutics have been conducted.

Integrin biology

Integrins are heterodimeric cell surface receptors and are key regulators affecting cell morphology, proliferation, survival and differentiation. Mutations in specific integrins or deregulated expressions are associated with a variety of diseases. Each integrin consists of α-subunit and a β-subunit, of which there are 18 and 8 variants, respectively, creating 24 known heterodimers. Integrins act as adhesion receptors with the unusual ability to signal in both directions across the plasma membrane. Integrins can therefore enable human cells to respond to changes in the extracellular environment (via outside-in signalling) and can influence the extracellular environment (via inside-out signalling). 

Notability, a wide variety of integrins are found in humans with diversity in the ligands they bind to; the tissue specific expression of specific integrins and the resulting signalling pathways involved in integrin activation, make these attractive drug targets for a number of different diseases. For example, the RGD-binding family of integrins recognises the amino acid binding motif Arg–Gly–Asp (RGD) in their endogenous ligands. Yet, despite their apparent similarity, these integrins can readily distinguish between different RGD-containing ECM proteins (e.g., vitronectin, TGFβ, fibronectin), and respond differently to the interaction with each one of them.

(Image source – Nature Reviews, Drug Discovery: Vol 21, January 2022)

Customizable Assays for Integrin Targeting in Drug Discovery

Integrins have become an attractive clinical target for a wide range of diseases, and recent clinical trials have underscored their potential. However, drug discovery in this area presents challenges due to the closely related integrin pairs present on cells, which require exceptional selectivity. To overcome this, a robust platform is needed to compare the inhibition of integrin adhesion across various integrin pairs.

(Image source – Integrins—mediators of cell-matrix and cell-cell adhesion – Lasker Foundation)

At o2h, our scientists are well-positioned to support collaborators by leveraging our extensive Integrated Drug Discovery (IDD) expertise at our UK and India sites. We have successfully developed cell-based assays that assess the target engagement of small molecules across different integrin targets. Building on this experience, we offer a highly customizable platform to determine compound potency in cell adhesion assays and ELISA against multiple integrin targets, enabling us to generate detailed specificity profiles.

Furthermore, we provide comprehensive compound characterization through bespoke cellular assays, utilizing flow cytometry and high-content imaging to evaluate their activity in a biological context. This integrated approach ensures precise, reliable data to guide your drug discovery efforts.

At o2h, we have developed and validated a customizable platform designed to assess inhibitors targeting the RGD family of integrin pairs. The data shown below on the left illustrates the effects of the commercially available inhibitor GSK3004348 on the adhesion of several integrin pairs, including αvβ6, αvβ8, αvβ1, and α5β1. The selectivity of the compound for αvβ6 is clearly evident, although it also maintains potent activity against αvβ8 and αvβ1.

The customizable nature of our assay also enables the investigation of compounds that do not only act as inhibitors of integrin binding. For example, at low concentrations, Cilengitide acts as an activator of the αvβ3 integrin, while at higher concentrations, it becomes an inhibitor, as shown in the figure above on the right. By adjusting assay conditions, we can capture this biphasic response—enhanced adhesion at low concentrations followed by inhibition at higher concentrations. These assays are fully established and ready to be performed, yet they can also be tailored to meet the specific requirements of your integrin biological studies.

To know more about the o2h discovery Biology capabilities  and our broader services, then please email us at discovery@o2h.com or visit – https://o2hdiscovery.co/biology/